DESCRIPTION: There is enormous clinical need for immediate point-of-care and continuous-monitoring diagnostics for brain injury. The state of the art ELISA (enzyme-linked immunosorbent assay immunoassay), SPR (surface plasmon resonance) and micro cantilevers are expensive, labor intensive, not point of care, impose excessive time delays, lack portability, and/or are not label-free. An electronic biosensor alternative for rapid, real time acute brain injury biomarker detection would fill an important clinical void. Organic thin film transistors (OTFTs) have been used for bio sensing in the last two decades, but with inadequate sensitivity. While nanowire sensors provide better sensitivity, they can be otherwise impractical. Therefore, it is highly desirable to develop improved biosensors based on organic or other macroscopic thin films. Herein we propose a highly sensitive OTFT sensor platform, using both p-channel and n-channel organic semiconductors, for detecting pg/mL protein levels essentially instantaneously with large, accessible sensing areas. Using both p- and n-channel transistors in a single sensor chip enables discrimination of possible electrical cross-talk and/or false-positive signals by correlating the response versus time from the two types of device elements. When integrated into a single inverter circuit, the two transistors can form a sensor with synergistic signal contributions from both, never before accomplished with proteins. We will use GFAP as the prototype analyst in order to advance progress toward practical and clinically relevant, real-time brain injury detection and the need for low concentration (40 pg/mL) clinical sensitivity. Innovations in capacitive coupling layers and receptor attachment will lead to such sensitivities, orders of magnitude higher than previously demonstrated for transistor-based sensing. This new overlayer chemistry, featuring fluoropolymer- hydrocarbon molecule dielectrics and both copolymer and dendritic receptor-linking layers, can also conceivably be applied to alternative semiconductors, including soluble organics to allow for greater printability of the devices, and inorganic semiconductors to allow for greater chemical resistance to aqueous and physiological solutions. Methods explored to increase sensitivity and durability will include: 1) determining the optimal thickness and improved composition of the fluoropolymer-hydrocarbon material to increase capacitance while maintaining resistive impedance to aqueous solutions; 2) increasing surface antibody density by linking antibodies to coupling groups via dendrimers; and 3) amplifying binding-induced electronic changes by catalytic degradation of the fluoropolymer in response to the binding. This last method is completely unprecedented in sensor literature, and could produce sub pg/mL sensitivities.